The clinical syndrome of AD is associated with A?-deposition and the dysfunction/death of populations of neurons in a variety of neural circuits and in multiple brain regions. While A?-production and deposition are generally thought to be essential early pathogenic events AD, in vivo relationship between A? and neurodegeneration is not well understood. While transgenic (Tg) mouse models of cerebral A? deposition have been important resources for studies relevant to AD pathogenesis, these Tg mouse models only exhibit modest degeneration of cortical and hippocampal neurons even with significant A? pathology. Thus, while progressive neurodegeneration and A?-deposition is a key feature of AD in humans, the in vivo mechanisms by which A?-deposition cause neurodegeneration remain elusive. We found that, in the APPswe/PS1?E9 Tg mice, A?-deposition is associated with degeneration of monoaminergic (MAergic) systems. Both 5-HT and TH+ fibers are lost from cortical and hippocampal regions with A?-deposition in the APPswe/PS1?E9 Tg mice. Significantly, progressive degeneration of MAergic fibers is followed by the degeneration of 5-HT and NA neurons in the brain stem. Thus, APPswe/PS1?E9 mice recapitulate the profound degeneration of 5-HT and NA systems seen in human AD. The loss of these neurons and their respective axonal projections play significant roles in AD-associated dysfunctions related to learning, memory, and affect. Our finding show that A?-deposition is sufficient to cause neurodegeneration and allows for further mechanistic analysis and testing of neuroprotective strategies. In this proposal, we will define in vivo pathologic relationship between A?- accumulation/deposition and neurodegeneration. We propose the following aims: 1) Determine the onset and selectivity of monoaminergic neurodegeneration in APPswe/PS1?E9 Tg mice. 2) Characterize monoaminergic neurodegeneration in the tTA/APP Tg mice. 3) Determine the causal relationship between brain A? production/accumulation and progressive degeneration of monoaminergic neurons. 4) Determine the relationship between tau expression and MAergic neurodegeneration. 5) Determine if the monoaminergic neurodegeneration (5-HT and/or NA) contributes to progression of A? pathology in APPswe/PS1?E9 Tg mice. PUBLIC HEALTH RELEVANCE: While amyloid pathology and neurodegeneration are key features of Alzheimer's Disease (AD), pathologic relationship between amyloid pathology and neurodegeneration is currently unclear. We will exploit our newly found neurodegeneration of monoaminergic neurons in transgenic mouse models of AD to determine the pathologic relationships between amyloid pathology and neurodegeneration in brain. Since amyloid pathology is a major target of AD therapeutics and because there is an ongoing neurodegeneration at diagnosis of AD, the proposed studies will have significant impact on understanding AD pathogenesis and on therapeutic approaches for AD.